Rapid preparation of cycloheptane ring from 1,2-diketone and bis(iodozincio)methane via oxy-cope rearrangement using microflow system

Article abstract of DOI:10.1246/cl.2012.628

Treatment of 1,6-dialkylhexa-1,5-diene-3,4-diones with bis(iodozincio) methane at-78 °C for several hours gave cisdialkenylcyclopropane-1,2-diols which rearranged into the zinc alkoxides of cis-5,6-dialkylcyclohepta-3,7-diene- 1,3-diol in good yields at r

Full text of DOI:10.1246/cl.2012.628

doi:10.1246/cl.2012.628
628
Published on the web June 2, 2012
Rapid Preparation of Cycloheptane Ring from 1,2-Diketone and Bis(iodozincio)methane
via Oxy-Cope Rearrangement Using Microflow System
Ryosuke Haraguchi, Yoshiaki Takada, and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoudai-Katsura, Nishikyo-ku, Kyoto 615-8510
(Received February 9, 2012; CL-120110; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp)
Treatment of 1,6-dialkylhexa-1,5-diene-3,4-diones with
As an addition of (1E,5E)-1,6-diphenylhexa-1,5-diene-3,4-
dione (2a) to bis(iodozincio)methane (1) at 0 °C gave a messy
mixture, the same procedure was examined at ¹20 °C. Although
the desired seven-membered ring product 5a was obtained in
28% yield, the aldol adduct of the zinc enolate 4a to the ketone
2a was also obtained in 40% yield (Scheme 2(1)). This result
implied that the first reaction, that is, the cyclopropanation of 2a
with 1 should complete before the start of Cope rearrangement to
prevent the side reactions. For this purpose, we treated the
diketone 2 with 1 at the lower temperature, which does not allow
the Cope rearrangement, for an appropriate period, until the
completion of cyclopropanation, and the resulting mixture was
warmed up to promote the rearrangement. Actually, as shown
in Scheme 2(2), (1E,5E)-1,6-diphenylhexa-1,5-diene-3,4-dione
(2a) was treated with 1 for 3 h at ¹78 °C, and the resulting
mixture was warmed up to 25 °C gradually to give the 7-
membered ring 5a in 78% yield.8
bis(iodozincio)methane at ¹78 °C for several hours gave cis-
dialkenylcyclopropane-1,2-diols which rearranged into the zinc
alkoxides of cis-5,6-dialkylcyclohepta-3,7-diene-1,3-diol in
good yields at room temperature as a one-pot reaction. The
reaction should be performed under the careful temperature
control. When the reaction was performed using a microflow
system, these two-step reactions were able to be performed in a
few seconds at room temperature.
A cycloheptane ring is often observed in natural products,
and its preparation has been well studied.1 To construct it,
cycloaddition reactions have been vigorously developed. In the
meanwhile, the cyclization strategy to a seven-membered ring
has been also examined in spite of unfavorable entropic factors.2
Among the cyclization method, the Cope rearrangement of cis-
divinylcyclopropane has been recognized as an efficient route to
obtain a cycloheptane skeleton. The disadvantageous entropic
factor to form a seven-membered ring is compensated with a
favorable configuration of cis-divinylcyclopropane. The diffi-
culty of the selective preparation of the cis-isomer of the
substrate, however, often causes the transformation to be less
valuable. Although some practical methods for the preparation
of the cis-isomer have been shown,3 most methods yielded the
trans-isomers that require a temperature of over 100 °C to
perform the Cope rearrangement.3d,4 During the course of our
research concerning bis(iodozincio)methane (1), we found the
nucleophilic cyclopropanation of 1,2-diketone, which gave cis-
cyclopropane-1,2-diol stereoselectively.5,6 When 1,6-dialkyl-
hexa-1,5-diene-3,4-diones 2 were treated with 1, the products
would be zinc alkoxides of cis-divinylcyclopropane-1,2-diols 3.
The alkoxides of cis-divinylcyclopropane derivatives 3 would
undergo the Cope rearrangement more rapidly due to acceler-
ation by the alkoxide groups (Scheme 1).7 These two reactions
may be performed sequentially without isolation.
The microflow system (space integration)9 may improve the
problem of the one-pot procedure described above, as it can
supply the minimum amount of the substrate to be consumed at
the micromixer. Thus, as shown in Scheme 3, we constructed a
microflow system consisting of two T-shaped SUS micromixers
(M1 and M2; Φ = 0.5 mm) and two SUS microtube reactors
(R1 and R2; Φ = 1.0 mm). A THF solution of 1 (0.16 M, 3.92
mL min¹1) and a THF solution of 1,2-diketone (0.09 M, 3.92
mL min¹1) were introduced by a syringe pump, and quenched
O
O
CH2(ZnI)2
(1.2 equiv)
1
H3O+
(1)
–20 °C
4 h
Ph
Ph
O
5a (28%)
Ph
Ph
O
O
O
CH2(ZnI)2
(1.2 equiv)
1
2a
H3O+
(2)
25 °C
–78 °C
1 h
3 h
Ph
Ph
5a (78%)
Scheme 2. Preparation of (5R,6S)-5,6-diphenylcycloheptane-
1,3-dione in a batch.
R2
R1
O
CH2(ZnI)2
1
R2
R1
stereoselective
cyclopropanation
OZnI
OZnI
O
CH2(ZnI)2
3
2
1
R1
stereospecific
Cope rearrangement
O
O
M1
O
R2
Ph
2a
O
O
M2
IZnO
OZnI
H3O+
Ph
2
side reaction
(aldol-type reaction)
Ph
Ph
O
3a
MeOH
R2
R1
R2
R1
5
4
Scheme 3. Microflow system for the preparation of cyclo-
heptane-1,3-dione.
Scheme 1. Syntheses of cycloheptane derivatives.
Chem. Lett. 2012, 41, 628-629
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

629
Table 1. Preparation of cycloheptane-1,3-diones using micro-
flow systema
Although the mixture containing a dienolate 4 was treated with
an excess amount of the ketone, the mono-aldol product was
obtained in a moderate yield.12-14
O
O
O
+ MeOH
Microreactor
R1
CH2(ZnI)2
R2
+
Thus, we can show an efficient use of a microflow system
for the transformation of divinyl-1,2-diketones into cyclohep-
tane-1,3-diones. While the classical batch reaction required a
careful temperature control to suppress the sidereaction between
the product and the starting substrate, the microflow system did
exclude the product from the reaction site continuously. The
one-pot reaction, which is difficult to control in the conventional
vessel, can be carried out efficiently using the space integration
concept.
25 °C, 6 s
1
2
O
R2
R1
5
2
Entry
Solvent
5/%
R1
R2
Ph
p-Anisyl
4-F-C6H4
2-Furyl
1
2
3
4
5
6
7
8
9
2a Ph
2b p-Anisyl
2c 4-F-C6H4
2d 2-Furyl
2e 4-t-Bu-C6H4 4-t-Bu-C6H4 THF
2f Me
2g Ph
2h p-Tol
2i p-Anisyl
THF
THF
THF
THF
85
55
82
77
74
51
Me
Ph
p-Tol
p-Anisyl
THF
References and Notes
1
C. H. Heathcock, S. L. Graham, M. C. Pirrung, F. Plavac, C. T. White,
in The Total Synthesis of Natural Products, ed. by J. ApSimon, Wiley,
New York, 1983, pp. 333-384.
CH2Cl2/THF >99
CH2Cl2/THF >99
CH2Cl2/THF
92
81
70
2
a) H. M. L. Davies, Tetrahedron 1993, 49, 5203. b) D. A. Foley, A. R.
Maguire, Tetrahedron 2010, 66, 1131. c) G. A. Molander, Acc. Chem.
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126, 11162.
10 2j 4-t-Bu-C6H4 4-t-Bu-C6H4 CH2Cl2/THF
11 2k Me Me CH2Cl2/THF
aThe reaction was performed with the microflow system in
Scheme 3: T-shaped SUS micromixer: M1 (inner diameter:
0.5 mm) and M2 (inner diameter: 0.5 mm), SUS microtube
reactor: R1 (Φ = 1.0 mm, length = 1 m), R2 (Φ = 1.0 mm,
3
4
a) H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev.
2003, 103, 977. b) K. Takeda, M. Takeda, A. Nakajima, E. Yoshii,
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8501. e) J. E. Baldwin, K. E. Gilbert, J. Am. Chem. Soc. 1976, 98,
8283.
length = 1 m), a solution of 1: 3.92 mL min¹1, 0.16 M; a
¹1
solution of 2: 3.92 mL min
,
0.09 M; methanol: 7.85
¹1
mL min
.
CH2(ZnI)2
1 (0.16 M in THF, 3.92 mLmin–1
M1
)
R1 (25 °C, 6s)
O
5
6
a) K. Ukai, K. Oshima, S. Matsubara, J. Am. Chem. Soc. 2000, 122,
12047. b) S. Matsubara, K. Ukai, H. Fushimi, Y. Yokota, H. Yoshino,
K. Oshima, K. Omoto, A. Ogawa, Y. Hioki, H. Fujimoto, Tetrahedron
2002, 58, 8255. c) K. Nomura, K. Asano, T. Kurahashi, S. Matsubara,
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Utimoto, K. Oshima, S. Matsubara, J. Am. Chem. Soc. 2010, 132,
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Ph
2a
2a (0.09 M in CH2Cl2, 3.92 mLmin–1
Ph
O
)
Ketone 6
O
O
OH
O
O
OH
O
O
OH
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
7a (81%)
7b (64%)
7c (78%)
Scheme 4. Sequential reaction using microflow system.11
10 M. Sada, S. Matsubara, Tetrahedron 2011, 67, 2612.
11 Crystallographic data have been deposited with The Cambridge
Crystallographic Data Centre: Deposition number CCDC-878671 for
compound 7a. Copies of the data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif (or from The Cambridge Crys-
tallographic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK;
e-mail: data_request@ccdc.cam.ac.uk).
12 Instead of ketone, an excess amount of aldehyde and the reaction
mixture from the microflow system gave the bis-aldol products 8a and
8b. The diastereomeric ratio was quite high, but the relative stereo-
chemistry has not been determined.
the excess amount of 1 with methanol in the M2. The residence
time was optimized by the length of the microtube reactor. As
shown in Table 1 (Entries 1-6), the products were obtained in
reasonable yields at 25 °C for 6 s continuously. In addition, the
system allowed us to use dichloromethane as a cosolvent. As the
structure change of the dizinc 1 in THF based on the Schlenk
equilibrium, which is often induced by an addition of any other
solvent, spoils the nucleophilicity,10 dichloromethane is difficult
to use as a cosolvent in a one-pot reaction. In the system, a THF
solution of 1 (0.16 M, 3.92 mL min¹1) and a dichloromethane
solution of 1,2-diketone (0.09 M, 3.92 mL min¹1) were intro-
duced by a syringe pump, and quenched the excess amount of
1 with methanol at the M2. The yields of the products were
improved dramatically (Entries 7-11, Table 1).
O
O
O
O
C3H7
OH
C3H7
HO
HO
OH
Ph
Ph
8b (99%)
Ph
Ph
8a (99%)
13 The low reactivity of the ketones 6 caused an isomerization of the
monoenolate, which had been formed by the reaction with an
equimolar ketone 6, into the stable 1,3-diketone enolate. It cannot
react with the ketone.
14 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
The further integrated syntheses were demonstrated in
Scheme 4. The reaction mixture, which ran out from the
microflow system, was treated with excess amount of a ketone.
Chem. Lett. 2012, 41, 628-629
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/